The present invention relates to novel prostaglandin derivatives, pharmaceutically acceptable salts thereof and hydrates thereof.
Since prostaglandin (hereinafter referred to as xe2x80x9cPGxe2x80x9d) exhibits various important physiological actions in a trace amount, the syntheses of a large number of derivatives from natural PGs and the biological activities have been investigated with the intention of a practical use as medicines and have been reported in many literatures, for example, Japanese Patent Kokai No. 52-100446 and U.S. Pat. No. 4,131,738.
PG and the derivatives thereof have biological actions such as a vasodilating action, a prophlogistic action, an inhibitory action of blood platelet aggregation, a uterine muscle contraction action, an intestine contraction action or a lowering action of intraocular pressure, and are useful for therapy or prevention of myocardial infarction, angina pectoris, arteriosclerosis, hypertension, labor induction, etc.
On the other hand, percutaneous transluminal coronary angioplasty (PTCA) has low invasiveness to the patient as a therapeutic modality of ischemic heart diseases and has an excellent initial therapy effect, therefore, it is a plasty which recently has rapidly been developed. However, there has been an unsolved drawback of causing restenosis of coronary artery at a frequency of 30-40% within a few months after PTCA.
The compounds which can control not only the migration from intima to mesothelium of vascular smooth muscle cells deeply associating with the onset of restenosis but also their growth in the mesothelium are greatly expected to be usable as drugs for prevention of the restenosis caused after PTCA. However, no clinically available drugs have been found.
An object of the present invention is to provide novel PG derivatives which exhibit excellent action in inhibiting the growth of vascular smooth muscle and are useful as a drug for prevention of restenosis after PTCA.
As a result of the continued extensive studies, the present inventors have found that the prostaglandin derivatives having a triple bond between the 13- and 14-positions and a hydroxyalkylthio group at the 11-position attain the above-mentioned object, and thereby the present invention has been accomplished.
That is, the present invention is directed to a prostaglandin derivative represented by the following Formula (I): 
wherein A is an ethylene group, a vinylene group, an ethynylene group, O(CH2)q or S(O)r(CH2)q, R1 is a C3-10 cycloalkyl group, a C1-4 alkyl-C3-10 cycloalkyl group, a C3-10 cycloalkyl-C1-4 alkyl group, a C1-10 alkyl group, a C1-10 alkyl group substituted with hydroxyl group(s) or C1-4 alkoxy group(s), a C2-10 alkenyl group, a C2-10 alkenyl group substituted with hydroxyl group(s) or C1-4 alkoxy group(s), a C2-10 alkynyl group, a C2-10 alkynyl group substituted with hydroxyl group(s) or C1-4 alkoxy group(s) or a bridged cyclic hydrocarbon group, R2 is a hydrogen atom, a C1-10 alkyl group or a C3-10 cycloalkyl group, m is an integer of 1 to 5, n is an integer of 1 to 4, p is 0, 1 or 2, q is an integer of 1 to 5 and r is 0, 1 or 2; a pharmaceutically acceptable salt thereof or a hydrate thereof.
Preferred compounds of the present invention are those of Formula (I) wherein R1 is a C5-10 alkyl group, a C5-10 alkyl group substituted with hydroxyl group(s) or C1-4 alkoxy group(s), a C5-10 alkenyl group, a C5-10 alkenyl group substituted with hydroxyl group(s) or C1-4 alkoxy group(s), a C5-10 alkynyl group, or a C5-10 alkynyl group substituted with hydroxyl group(s) or C1-4 alkoxy group(s), and q is 1 or 2, and specially preferred compounds are those of Formula (I) wherein m is an integer of 2 to 4, and n is 2 or 3.
Furthermore, the present invention is directed to a pharmaceutical preparation which comprises as an effective ingredient a compound represented by Formula (I), a pharmaceutically acceptable salt thereof or a hydrate thereof.
The terms used in the present invention are defined as follows:
The vinylene group refers to a cis- or trans-vinylene group.
The C3-10 cycloalkyl group means a cycloalkyl group having 3 to 10 carbon atoms, and examples thereof are a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group.
The C1-4 alkyl-C3-10 cycloalkyl group means a cycloalkyl group having 3 to 10 carbon atoms substituted with a straight or branched alkyl group having 1 to 4 carbon atoms, and examples thereof are a methylcyclopropyl group, a methylcyclohexyl group and an ethylcyclohexyl group.
The C3-10 cycloalkyl-C1-4 alkyl group means a straight or branched alkyl group having 1 to 4 carbon atoms substituted with a cycloalkyl group having 3 to 10 carbon atoms, and examples thereof are a cyclopropylmethyl group, cyclobutylmethyl group, a cyclopentylmethyl group, a cyclopentylethyl group, a cyclohexylmethyl group, a cyclohexylethyl group and a cycloheptylmethyl group.
The C1-10 alkyl group means a straight or branched alkyl group having 1 to 10 carbon atoms, and examples thereof are a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopropyl group, a hexyl group, a heptyl group, an octyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 1-methylhexyl group, a 2-methylhexyl group, a 2,4-dimethylpentyl group, a 2-ethylpentyl group, a 2-methylheptyl group, a 2-ethylhexyl group, a 2-propylpentyl group, a 2-propylhexyl group, a 2,6-dimethylheptyl group, a nonyl group and a decyl group.
The C1-10 alkyl group substituted with hydroxyl group(s) or C1-4 alkoxy group(s) means a straight or branched alkyl group having 1 to 10 carbon atoms substituted with hydroxyl group(s) or straight or branched alkoxy group(s) having 1 to 4 carbon atoms, and examples thereof are a 5-hydroxy-2-methylpentyl group, a 4,5-dihydroxypentyl group, a 5-methoxy-2-methylpentyl group, a 4-ethoxybutyl group or a 4-allyloxybutyl group.
The C2-10 alkenyl group means a straight or branched alkenyl group having 2 to 10 carbon atoms, and examples thereof are a vinyl group, an allyl group, a 2-propenyl group, a 3-pentenyl group, a 4-hexenyl group, a 5-heptenyl group, a 4-methyl-3-pentenyl group, a 2,4-dimethyl-3-pentenyl group, a 6-methyl-5-heptenyl group and a 2,6-dimethyl-5-heptenyl group.
The C2-10 alkenyl group substituted with hydroxyl group(s) or C1-4 alkoxy group(s) means a straight or branched alkenyl group having 2 to 10 carbon atoms substituted with hydroxyl group(s) or straight or branched alkoxy group(s) having 1 to 4 carbon atoms, and examples thereof are a 6-hydroxy-2-methyl-3-hexenyl group and a 6-methoxy-3-hexenyl group.
The C2-10 alkynyl group means a straight or branched alkynyl group having 2 to 10 carbon atoms, and examples thereof are an ethynyl group, a 2-propynyl group, a 3-pentynyl group, a 3-hexynyl group, a 4-hexynyl group, a 1-methylpent-3-ynyl group, a 2-methylpent-3-ynyl group, a 1-methylhex-3-ynyl group and a 2-methylhex-3-ynyl group.
The C2-10 alkynyl group substituted with hydroxyl group(s) or C1-4 alkoxy group(s) means a straight or branched alkynyl group having 2 to 10 carbon atoms substituted with hydroxyl group(s) or straight or branched alkoxy group(s) having 1 to 4 carbon atoms, and examples thereof are a 5-hydroxy-1-methylpent-3-ynyl group and a 6-methoxy-3-hexynyl group.
Examples of the bridged cyclic hydrocarbon group are a bornyl group, a norbornyl group, an adamantyl group, a pinanyl group, a thujyl group, caryl group and a camphanyl group.
Examples of the pharmaceutically acceptable salt are salts with alkali metal (e.g. sodium or potassium), alkali earth metal (e.g. calcium or magnesium), ammonia, methylamine, dimethylamine, cyclopentylamine, benzylamine, piperidine, monoethanolamine, diethanolamine, monomethyl-monoethanolamine, tromethamine, lysine, a tetraalkyl ammonium and tris(hydroxymethyl)aminomethane.
The compounds of Formula (I) can be prepared, for example, by the methods summarized by the following reaction scheme (wherein, A1 is an ethylene group, a vinylene group, an ethynylene group, O(CH2)q or S(CH2)q, A2 is an ethylene group, a vinylene group, an ethynylene group, O(CH2)q or S(O)r1(CH2)q, R3 is R2 other than a hydrogen atom, p1 is 1 or 2, r1 is 1 or 2, and R1, m, n and q are as defined above). 
The production processes of the compounds of the present invention are below illustrated according to the reaction scheme.
(1) At first, a compound of Formula (II) is prepared according to the methods described in Japanese Patent No. 2641622 (WO92/18472), Japanese Patent Kokai Nos. 4-818473, 5-117230, 5-294924 or 6-192219 or the modification thereof, it is then subjected to dehydration in an organic solvent (e.g. methanol, ethanol, ethyl acetate or dioxane), water or a mixture thereof by using an organic acid (e.g. formic acid or acetic acid) or an inorganic acid (e.g. sulfuric acid or hydrochloric acid) at a temperature of 0 to 60xc2x0 C. to give a compound of Formula (III).
(2) The compound of Formula (III) is reacted with a compound of Formula (IV) in an inert solvent (e.g. benzene, toluene, xylene, n-hexane, n-pentane or acetone) at a temperature of xe2x88x9278 to 100xc2x0 C. to give compounds of formulae (Ia) and (Iaxe2x80x2) of the present invention which are stereoisomers at the 11-position. In this reaction, can be optionally added an amine (e.g. triethylamine or diisobutylamine) or a radical generating agent (e.g. azobisisobutyronitrile, azobiscyclohexanecarbonitrile, benzoyl peroxide or triethylborane). These compounds of formulae (Ia) and (Iaxe2x80x2) can be purified according to a conventional separation procedure such as column chromatography.
(3) The compound of Formula (Ia) (or (Iaxe2x80x2)) is hydrolyzed by an enzyme in a buffer solution such as phosphate buffer or tris-hydrochloride buffer, if necessary, by using an organic solvent (e.g. a water-miscible solvent such as acetone, methanol or ethanol) to give a compound of Formula (Ib) (or (Ibxe2x80x2)) of the present invention.
Examples of the enzyme to be used are enzymes produced by microorganisms (e.g. enzymes produced by microorganisms belonging to Candida sp. or Pseudomonas sp.) and enzymes prepared from animal organs (e.g. enzymes prepared from pig liver or pig pancreas). Commercially available enzymes are, for example, lipase VII (derived from microorganism of Candida sp.; Sigma Co.), lipase AY (derived from microorganism of Candida sp.; Amano Pharmaceutical Co.), lipase PS (derived from microorganism of Pseudomonas sp.; Amano Pharmaceutical Co.), lipase MF (derived from microorganism of Pseudomonas sp.; Amano Pharmaceutical Co.), PLE (prepared from pig liver; Sigma Co.), lipase II (prepared from pig pancreas; Sigma Co.) or lipoprotein lipase (prepared from pig pancreas; Tokyo Kasei Kogyo Co.).
The amount of the enzyme to be used, while depending on the potency of the enzyme and the amount of the substrate (the compound of Formula (Ia)), is usually 0.1 to 20 parts by weight based on the substrate, and the reaction temperature is from 25 to 50xc2x0 C., preferably 30 to 40xc2x0 C.
(4) The compound of Formula (Ia) or (Iaxe2x80x2) is oxidized using an oxidant such as sodium metaperiodate, hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid or tert-butyl hydroxyperoxide in diethyl ether, methanol, ethanol, methylene chloride, water or a mixture thereof at a temperature of xe2x88x9220 to 50xc2x0 C. to give a compound of Formula (Ic) or (Icxe2x80x2) of the present invention.
(5) The compound of Formula (Ib) or (Ibxe2x80x2) is oxidized in the manner similar to as described in the above (4) to give a compound of Formula (Id) or (Idxe2x80x2) of the present invention.
The pharmaceutical preparations of the present invention can be administered systemically or topically; orally or parenterally such as rectally, subcutaneously, intramuscularly, intravenously or percutaneously, and preferably orally or intravenously.
The pharmaceutical preparations of the present invention can be produced by containing a pharmaceutically acceptable carrier. Specifically, for oral administration can be prepared the form of tablets, powders, granules, fine powders, capsules, solutions, emulsions or suspensions by mixing an excipient, a binding agent, a disintegrator, a filler, a coating agent or a sugar coating agent, or by mixing an aqueous or non-aqueous solvent according to conventional manners. For intravenous administration can be prepared the form of aqueous or non-aqueous solutions, emulsions, suspensions or solid preparations to be dissolved in a solvent for injection immediately before use according to conventional manners. Furthermore, the compounds of the present invention can be formulated by forming the inclusion compounds with xcex1-, xcex2- or xcex3-cyclodextrin, or methylated cyclodextrin, and can be administered by injection in the form of aqueous or non-aqueous solutions, emulsions or suspensions.
The dose of the compound of the present invention is varied by the disease, conditions, body weight, age, sex, administration route, etc., but it is preferably from 0.1 ng to 10 mg/day per adult in a single dose or divided doses. When used as a drug for growth inhibition of vascular smooth muscle, the dose is preferably from 1 ng to 1 mg/day per adult in a single or divided doses.
Representative compounds of Formula (I) of the present invention are as described follows: